2-Decarboxy-2-tetrazolyl-trans-2,3,4,5-tetradehydro-PGI1 compounds

ABSTRACT

The present invention relates to novel 2-decarboxy-2-tetrazolyl-trans-2,3,4,5-tetradehydro-PGI 1  compounds, which are useful for inducing a variety of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful pharmacological agents for the same purposes for which prostacyclin is employed.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of U.S. Ser. No.936,295, filed Aug. 23, 1978, now U.S. Pat. No. 4,202,972 issued May 13,1980; which is a divisional application of U.S. Ser. No. 819,856, filedJuly 28, 1977, now U.S. Pat. No. 4,123,441; which is acontinuation-in-part application of U.S. Ser. No. 725,546, filed Sept.22, 1976, now abandoned; which is a continuation-in-part application ofU.S. Ser. No. 716,960, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-decarboxy-2-tetrazolyl-trans-2,3,4,5-tetradehydro-PGI₁ -compounds,which are useful for inducing a variety of prostacyclin-likepharmacological effects. Accordingly, these compounds are usefulpharmacological agents for the same purposes for which prostacyclin isemployed.

The essential material constituting a disclosure of the preparation anduse of the novel compounds of the present invention is incorporated hereby reference from U.S. Pat. No. 4,123,441.

SUMMARY OF THE INVENTION

The present invention particularly provides: a 4Z compound of theformula ##STR1##

wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;

wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; and

wherein R₄ is

(1) --CR₅ R₆ --C_(g) H_(2g) ═CH₃

(2) --CR₅ R₆ --Z--(Ph)

(3) cis--CH₂ --CH═CH--CH₂ CH₃

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s, wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ isalkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3,with the proviso that not more than two T's are other than alkyl andwhen s is 2 or 3 the T's are either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof; and

a 4E compound of the formula ##STR2##

wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;

wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; and

wherein R₄ is

(1) --CR₅ R₆ --C_(g) H_(2g) ═CH₃

(2) --CR₅ R₆ --Z--(Ph)

(3) cis--CH₂ --CH═CH--CH₂ CH₃

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s, wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ isalkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3,with the proviso that not more than two T's are other than alkyl andwhen s is 2 or 3 the T's are either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

With regard to the divalent substituents described in the claims, e.g.,Q and W₁, these divalent radicals are defined as α-R_(i) :β-R_(j), whereR_(i) represents a substituent of the divalent moiety of the alphaconfiguration with respect to the cyclopentane and R_(j) represents asubstituent of the divalent moiety of the beta configuration withrespect to the cyclopentane ring. Accordingly, when Q is defined asα-OH:β-R₈, the hydroxy of the Q moiety is in the alpha configuration,i.e., as in prostacyclin, and the R₈ substituent is in the betaconfiguration. Not all carbon atoms to which such divalent moieties areattached represent asymmetric centers. For example, when both valencebonds are to hydrogen (e.g., W₁ or Q is α-H:β-H), then no assymetriccenter is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemicalcompounds:

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ² -PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-(15S)-15-methyl-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16,16-dimethyl-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-13,14-dihydro-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ.tbd.4-trans-Δ²-17-phenyl-18,19,20-trinor-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16-phenoxy-17,18,19,20-tetranor-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16-(α,α,α-trifluoro-p-tolyloxy)-17,18,19,20-tetranor-PGF₁ ;

2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF₁ ; and

2-Decarboxy-2-tetrazolyl-(4E)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ² -PGF₁.

I claim:
 1. A 4Z compound of the formula ##STR3## wherein W₁ isα-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;wherein Q isoxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH wherein R₈ is hydrogen or alkyl ofone to 4 carbon atoms, inclusive; andwherein R₄ is (1) --CR₅ R₆ --C_(g)H_(2g) ═CH₃ (2) --CR₅ R₆ --Z--(Ph) (3) cis--CH₂ --CH═CH--CH₂ CH₃ whereinC_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with oneto 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- andterminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s, wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ isalkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3,with the proviso that not more than two T's are other than alkyl andwhen s is 2 or 3 the T's are either the same or different; and wherein Xis (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂CH₂ --;including the lower alkanoates thereof.
 2. A compound accordingto claim 1, wherein Q is α-OH:β-R₈ or α-R₈ :β-OH, and W₁ is α-OH:β-H,α-H:β-OH, or α-H:β-H.
 3. A compound according to claim 2, wherein W₁ isα-OH:β-H.
 4. A compound according to claim 3, wherein α is α-OH:β-R₈. 5.A compound according to claim 4, wherein R₄ is --CR₅ R₆ --C_(g) H_(2g)--CH₃.
 6. A compound according to claim 4, wherein R₄ is --CR₅ R₆ (Ph).7. 2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ² -PGF₁,a compound according to claim
 6. 8.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-(15S)-15-methyl-PGF₁, a compound according to claim
 6. 9.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16,16-dimethyl-PGF₁, a compound according to claim
 6. 10.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-13,14-dihydro-PGF₁, a compound according to claim
 6. 11.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-17-phenyl-18,19,20-trinor-PGF₁, a compound according to claim
 6. 12.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16-phenoxy-17,18,19,20-tetranor-PGF₁, a compound according to claim 6.13. 2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF₁, a compound according toclaim
 6. 14. 2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴-trans-Δ² -16-(α,α,α-trifluoro-p-tolyloxy)-17,18,19,20-tetranor-PGF₁, acompound according to claim
 6. 15.2-Decarboxy-2-tetrazolyl-(4Z)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ²-13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF₁, a compoundaccording to claim
 6. 16. A 4E compound of the formula ##STR4## whereinW₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;whereinQ is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH wherein R₈ is hydrogen oralkyl of one to 4 carbon atoms, inclusive; andwherein R₄ is (1) --CR₅ R₆--C_(g) H_(2g) ═CH₃ (2) --CR₅ R₆ --Z--(Ph) (3) cis--CH₂ --CH═CH--CH₂ CH₃wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s, wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ isalkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3,with the proviso that not more than two T's are other than alkyl andwhen s is 2 or 3 the T's are either the same or different; and wherein Xis (1) trans-CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂CH₂ --;including the lower alkanoates thereof.
 17. A compound accordingto claim 16, wherein Q is α-OH:β-R₈, wherein W₁ is β-OH:β-H, and whereinR₄ is --CR₅ R₆ --C_(g) H_(2g) --CH₃. 18.2-Decarboxy-2-tetrazolyl-(4E)-9-deoxy-5,9α-epoxy-Δ⁴ -trans-Δ² -PGF₁, acompound according to claim 16.